Morphine solution



To all whom "it camera. I

I g i he 1,563,086 UNITEDISTATES PATENT OFFICE.

cnannnsw. Hoornn, or JAMAICA,'NEW Yonx, ASSIGNOR To 11. A. un'rz LABORA- ronms, 1n on NEW roman. Y., A conrona'rron or raw Yonx.

uonrnmn SOLUTION.

Noni-swing.

Be it known that 1, CHARLES a citizen of the United States, and resident of Jamaica, County of Queens, and State of New York, have invented certain new and useful Improvements Relating to Morphine f ments whereby such solutions arefrendered. sterile and stable. Also according to m Solutions, of-which the following is a specification.

'My inventi'en relates to morphine' solutions and more particularly to improve-- improvements in a preferredform thereo the solutions are characterized ,by great analgesic potency. Further-land more specific objects, features and advantages will more clearly appear from the detail descriptive given below. 7 v

l The hypodermic injection of morphine in aqueous solution has achieved great therap peutic importance and has'beenused unimversally asan analgesic agent in surgery andfor the alleviation of human s'ufl'ering in disease. Heretofore it has been necessary to prepare the" hypodermic solution by dissolving a morphine tablet in a small amount "of boiling water. immediately before use.

These solutions are not necessarily sterile and as a result frequently give rise to painful tissue reactions at the site or the injection' with the formation-of infiltrates, ne-

. .croses,'and at times even abscesses. The solutions are so prepared immediately before use because morphine in aqueous solution decomposes on standing due to the action of,

bacteria and molds; and furthermore such aqueous solutions of morphine are not, ca-

pable of being sterilized by boiling or autoclaving without oxidizing the morphine or if it were used inthe changing it so that it would not have the changed condition,

1 desired analgesic effect, since the oxidation products of morphine. are therapeutical1y relatively inert.1 Both of these character-1 istics are such as to prevent the employment; of morphine in ready 7 either m'the-hospita to ;use stock solutions a morphine solution is produced which-is notonly sterile, but it may be kept for long: riods of time ready to mess stocksoziiition ofmorphine and it does not pro duce the painful tissue reactions at the site "ofinjection as heretofore. I have discov-.

ered that such a stable sterile solution of :Heom,

or as a stock" in trade.- a According to my improvements, however,

Application filed October a; 1924. semi No. 742,425.?

morphine can be prepared by including therein a stabilizing agent preferably in the nature of a reducing agent which so affects the morphine as to prevent its oxidation and therefore its deterioration when sterilized by boiling or autoclavin When .1 refer to morphine or solution 0 morphine it will be understood that this includes the various forms in which morphine is or may be used for the purposes in question, e.-' g'. in the form of any of its salts. For a stabilizing'or reducing agi'ent I prefer to use sodium bisulphite an the solution is preferably made by dissolving a sufficient quantity of the sodiumbisulphite in the morphine solution to prevent the oxidation which normally occurs when morphine in aqueous solution is boiled. However, other reducing or stabilizing agents may be employed, for example other sulphur compounds and particularly the sulphurous compounds such as hyposulphurous acid or its-salts, sulphurous acid, other bisulphites, sulphur dioxide, etc. These stabilizing or reducing agents when so employed have thecharacteristic of being able to practically prevent the oxidation which occurs in aqueous solutions of morphine when the solution is sterilized by boiling or autoclaving. The introduction of such reducing agents prevents'this oxidation and thereby produces a desired stabilized solution, the morphine remaining stable in its solution form.' In producing such a solusulphite, a suitable proportion for the solution is as follows: Morphite sulphate 0.5

gram, sodium bisulphite 0.1 gram, and distilled water in suflicient quantity to make cubic centimeters. While these proportions f give excellent results I have. used slightly smaller quantities of the stabilizer as well as larger' quantities without harmful effect upon the working qualities of the solution.

In order tobettei' sterility, I. prefer to fill glass ampules. of the desired volume with the freshly preparedsolution, seal the ampules off with thejaidof a blowpipein the manner well understoodjby those skilled in pules in' boiling ywater -for 15 to 30 minutes 'the art, and then submerge the sealed amllO for alike period. This thoroughly sterilizes the solutions in the sealed ampules and the with the solution remaining 1n stable sterile condition. By sterilizing the solution while sealed in ampules. as above described, any accidental contamination after sterilization is prevented'and also all loss by evaporation of any of the ingredients of the solution 1s prevented so that by thus holding the solu tion in sealed ampules the stabilizing agent is made more effective. I also believe. the stabilizing agent in addition to the function noted also acts to reduce the time 1' uired to boil the solution in sterilizing an also tends to maintain the solution sterile after the ampules have been opened. I

I have also found that the. addition of magnesium sulphate or. equivalent magnesium salt to the morphine solution acts as an additional safeguard against oxidation. of the morphine during sterilization. In

. some casesthis may besubstituted entirely for the sulphur reducing agent. When using magnesium sulphate in the solution, I preferably use from 25 to 50 grams of magnesium sul hate (M SO FZH O) in the 100 c. c. of morphine solution above mentioned. However, the proportion ofmagnesium salt employed may vary even more greatly. The magnesium sulphate I believe not only acts as an aid to the stabilizingagent in preventin oxidation or deterioration of the morphine solution, since I find that the amount of stabilizer can be reduced in th e presence of magnesium sulphate, but it also seems to act synergistically on the morphine, intensifying the therapeutic effect of themor hine.

Instead of using the magnesium salt in the solution or in addition thereto, I may add an alkamine ester of aromatic acid of the class of anaesthetics which are adapted for use as local anaesthetics, 7 such as chloride of para-amino-benzoyl-diethylamino-ethanol (novocaine). This also appears to act synergistically on the morphine increasing greatly the analgesic potency of the solution when injected hypodermically without increasing the toxicity of the solution. This combination also prevents the salivation, nausea and vomiting that frequently follow the use of simple morphine solutions. By means of animal experiments I have also been able to show that it prevents the development of tolerance to the morphine and therefore should counteract the habit forming roperties of the drug I find that when the above de- '.scribed-=solution is used as a preliminary medication for surgical operations, postoperative analgesia is seldom required. The

monohydroaddition of the novocaine or other alkamine ester of an aromatic acid seems to increase the action of both the morphine and mag nesium sulphate, greatly intensifying the therapeutic effect of the solution. The amount of alkamine ester of an aromatic acid to be used may vary considerably according to conditions. \Vhen using novocaine I prefer to use the same in proportion of about 2.5 grams in the 100 cubic centimeters of morphine solution above described. I have obtained excellent results'with other proportions of novocaine, varying from 2 to 10 grams in the 100 cubic centimeters solution above described. As above indicated other alkamine esters of aromatic acids can be used in place of the novocaine and other magnesium salts such as magnesium chloride may be used in place of the magnesium sulphate. I

Morphine solutions which I made and put T up in ampules as above described are now approximately a year old, and they are still Water clear and have retained full analgesic potency; .I have had such solutions tested 'for various purposes for which morphine produce ready to use aqueous solutions of morphine for analgesic urposes which are far superior to the morphine solutions heretofore employed and which do not produce the painful tissue reaction when injected hypodermically'. Also I have eliminated the oxidation which has heretofore taken lace when such solutions are sterilized by boiling or autoclaving and I have rendered the solution stable so that it may be employed as a stock solution either in the hospital or as a stock in trade.

While I have described my improvements in great detail and with-respect to preferred forms thereof, I do not desire to be limited to such details or forms since many modifications and changes may be made, the proportions may be varied and certain of the ingredients omitted to meet various uses to which the solution is to be put and the invention may be embodied in widely differout forms without departing from the spirit and S00 e thereof in its broader aspects.

Hence desire to cover all modifications andforms coming within the scope or language'of any one or more of the appended vent oxidation of t e morphine.

2. A solution of morphine sealed in an vocaine to intensify the therapeutic efiect of I ampule with a sulphur reducing agent adapted to prevent oxidation when heated to sterilize.

3. A solution of morphine and magnesium sulphate containing a sulphur reducing agent to stabilize and prevent oxidation of sulphur reducing agent to stabilize andprevent oxidation of the morphine, and no the morphine.

9. A solut1on of morphine and magnesium" sulphate and novocaine to intensify. the therapeutic effect of the morphine when injected hypodermaticall the solution being sealed in a glass amp 0.

10. A solution of morphine containing a sulphur reducing agent and a magnesium salt and novocaine to intensify the therapeutic effect of the morphine when injected ypodermatically. 11. A solution of morphine and magnesium sulphate and novocaine containing a sulphur reducing agent to stabilize and prevent oxidation of the morphine.

12. The method of preparing morphine solution which consists in making a solution of morphine, ma nesium sulphate and novocaine, sealing o the solution in ampulesand then heating the solution in the ampules to sterilize the same. Y a

13. A sterile stable solution of morphine containing a stabilizing agent consisting of a salt of a sulphurous acid to prevent oxidation of the mor hine in solution on boiling to pseudo-mor ine.

' 14..The met od of preparing morphine solutions which consists in making a solu tion of morphine containing a sulphur sta-' bilizing agent, sealing off the solution in glass ampules and then heating the solution in the ampules to sterilize the same.

proportion of about 100 c. e. of water, about O/5 gram morphine, 2.5 gram of novocaine, about 50 grams of magnesium sulphate and about 0.1 gram of sodium bisulphite.

In testimony'whereof I have signed my name to this specification.

CHARLES W. scores.

15. A sterile stable solution of. morphine in water containing novocaine and magnesiumsulphate and sodium bisulphite in the 0 

